Two N-acylphenylalanine derivatives have recently been synthesized as potential antisickling agents. This new class of very hydrophobic analogues has resulted in increased potency in the Csat assay for inhibition of the gelation of HbS. For example, one analogue, SL-Phe, has been found to be more than two orders of magnitude more potent than the amino acid phenylalanine itself. This very significant "leap" in potency is coupled with good erythrocyte permeability without apparent adverse effects on the erythrocytes. Preliminary studies did not reveal any binding interaction with the erythrocyte membrane. The antigelation activity of this series of analogues is apparently due to non-covalent interation(s) on the hemoglobin surface that interfere with the aggregation process which leads to HbS fiber formation and eventual sickling in SS erythrocytes. The preliminary results described above have prompted us to propose the further investigation of these N-acylated phenylalanine derivatives in order to obtain an analogue or analogues that would prove suitable for further development as a therapeutically useful agent for the treatment of sickle cell anemia. Therefore, we propose to snythesize a series of N-acylphenylalanine derivatives that are considerably more hydrophobic than phenylalanine. These analogues will then be evaluated by a series of in vitro and in vivo methods in order to select the most suitable agents for further investigation. The in vitro studies will include 1) the Csat assay, 2) the oxygen affinity measurements on HbS and in SS erythrocytes, 3) the mean corpuscular hemoglobin concentrations (MCHC) 4) red cell metabolism, 5) erythrocyte permeability and potential internal concentration, 6) compound stability in whole blood, 7) morphology of erythrocytes by scanning electron microscopy (SEM), and 8) erythrocyte heterogeneity and survival. The in vivo evaluation will include determinations of 1) acute and sub-acute toxicity, 2) cursory post-mortem examinations, and 3) preliminary studies of the half-life and extent of metabolism of the most promising analogues. The preliminary results indicate that the potency of this new class of non-covalent HbS gelation inhibitors will be suitable for the achievement of therapeutically effective blood levels. Investigations of the actual mechanism of action of these analogues and whether or not specific binding sites or "receptors" exist on the hemoglobin surface can emanate from these proposed studies once suitable highly active compounds have been identified.